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Current Research and Scholarly Interests

My research focuses on two main areas: 1) the structural organization and function of central neural pathways (e.g. of the spinal cord, brainstem, thalamus and cortex) that underlie directed manual behavior, and 2) the capacity of these central neural pathways (circuits) to compensate/adapt following localized injury. Our laboratory uses neuroanatomical, electrophysiological and behavioural approaches to look at the sensorimotor systems of nonhuman primates, and to examine the neural basis for functional 'recovery’ observed following the selective disruption of pathways mediating fine finger control.We are also interested in the presence and role of adult neurogenesis in the CNS following injury.

Abstract

The corticospinal tract in the macaque and human forms the major descending pathway involved in volitional hand movements. Following a unilateral cervical dorsal root lesion, by which sensory input to the first three digits (D1-D3) is removed, monkeys are initially unable to perform a grasp retrieval task requiring sensory feedback. Over several months, however, they recover much of this capability. Past studies in our laboratory have identified a number of changes in the afferent circuitry that occur as function returns, but do changes to the efferent pathways also contribute to compensatory recovery? In this study we examined the role of the corticospinal tract in pathway reorganization following a unilateral cervical dorsal rhizotomy. Several months after animals received a lesion, the corticospinal pathways originating in the primary somatosensory and motor cortex were labeled, and terminal distribution patterns on the two sides of the cervical cord were compared. Tracers were injected only into the region of D1-D3 representation (identified electrophysiologically). We observed a strikingly different terminal labeling pattern post lesion for projections originating in the somatosensory versus motor cortex. The terminal territory from the somatosensory cortex was significantly smaller compared with the contralateral side (area mean = 0.30 vs. 0.55 mm2), indicating retraction or atrophy of terminals. In contrast, the terminal territory from the motor cortex did not shrink, and in three of four animals, aberrant terminal label was observed in the dorsal horn ipsilateral to the lesion, indicating sprouting. These differences suggest that cortical regions play a different role in post-injury recovery

Abstract

Adult neurogenesis remains controversial in the cerebral cortex. We have previously shown in monkeys and rats that reactive neurogenesis occurs in the spinal dorsal horn 6-8 weeks after a cervical dorsal rhizotomy. Here, in three monkeys with the same lesion, we asked whether it also occurs coincidentally in the corresponding primary somatosensory and motor cortex, where significant topographic and neuronal reorganization is known to occur. Monkeys (male Macaca fascicularis) were given 5-bromo-2-deoxyuridine (BrdU) injections 2-3 weeks after the rhizotomy, and were perfused 4-6 weeks later. Cells colabeled for BrdU and five different neuronal markers were observed within the primary somatosensory and motor cortex, and their distributions were compared bilaterally. Cells colabeled with BrdU and the astrocytic marker glial fibrillary acidic protein (GFAP) were also quantified for comparison. A significant number of BrdU/NeuN- and BrdU/calbindin-colabeled cells were observed in topographically reorganized cortex. Small numbers of BrdU/GFAP-colabeled cells were also consistently observed bilaterally, but these cells were never colabeled with any of the neuronal markers. Of the cells colabeled with BrdU and a neuronal marker, at least half had an inhibitory phenotype. However, excitatory pyramidal neurons were also identified with classic pyramidal morphology. Cortical neurogenesis was not observed in other cortical regions. It was also not observed in the primary sensorimotor, prefrontal, or posterior parietal cortex in an additional control monkey (male Macaca fascicularis) that had no surgical intervention. Our findings provide evidence for reactive endogenous cortical neurogenesis after a dorsal rhizotomy, which may play a role in functional recovery.

Abstract

Studies in monkeys have shown substantial neuronal reorganization and behavioral recovery during the months following a cervical dorsal root lesion (DRL; Darian-Smith [2004] J. Comp. Neurol. 470:134-150; Darian-Smith and Ciferri [2005] J. Comp. Neurol. 491:27-45, [2006] J. Comp. Neurol. 498:552-565). The goal of the present study was to identify ultrastructural synaptic changes post-DRL within the dorsal horn (DH). Two monkeys received a unilateral DRL, as described previously (Darian-Smith and Brown [2000] Nat. Neurosci. 3:476-481), which removed cutaneous and proprioceptive input from the thumb, index finger, and middle finger. Six weeks before terminating the experiment at 4 post-DRL months, hand representation was mapped electrophysiologically within the somatosensory cortex, and anterograde tracers were injected into reactivated cortex to label corticospinal terminals. Sections were collected through the spinal lesion zone. Corticospinal terminals and inhibitory profiles were visualized by using preembedding immunohistochemistry and postembedding gamma-aminobutyric acid (GABA) immunostaining, respectively. Synaptic elements were systematically counted through the superficial DH and included synaptic profiles with round vesicles (R), pleomorphic flattened vesicles (F; presumed inhibitory synapses), similar synapses immunolabeled for GABA (F-GABA), primary afferent synapses (C-type), synapses with dense-cored vesicles (D, mostly primary afferents), and presynaptic dendrites of interneurons (PSD). Synapse types were compared bilaterally via ANOVAs. As expected, we found a significant drop in C-type profiles on the lesioned side ( approximately 16% of contralateral), and R profiles did not differ bilaterally. More surprising was a significant increase in the number of F profiles ( approximately 170% of contralateral) and F-GABA profiles ( approximately 315% of contralateral) on the side of the lesion. Our results demonstrate a striking increase in the inhibitory circuitry within the deafferented DH.

Abstract

Spinal cord injury research has greatly expanded in recent years, but our understanding of the mechanisms that underlie the functional recovery that can occur over the weeks and months following the initial injury, is far from complete. To grasp the scope of the problem, it is important to begin by defining the sensorimotor pathways that might be involved by a spinal injury. This is done in the rodent and nonhuman primate, which are two of the most commonly used animal models in basic and translational spinal injury research. Many of the better known experimentally induced models are then reviewed in terms of the pathways they involve and the reorganization and recovery that have been shown to follow. The better understood neuronal mechanisms mediating such post-injury plasticity, including dendritic spine growth and axonal sprouting, are then examined.

Abstract

Neurogenesis has not been shown in the primate spinal cord and the conditions for its induction following spinal injury are not known. In the first part of this study, we report neurogenesis in the cervical spinal dorsal horn in adult monkeys 6-8 weeks after receiving a well-defined cervical dorsal rhizotomy (DRL). 5-bromo-2-deoxyuridine (BrdU) was administered 2-4 weeks following the lesion. Cells colabeled with BrdU and five different neuronal markers were observed in the peri-lesion dorsal horn 4-5 weeks after BrdU injection. Those colabeled with BrdU and neuron-specific nuclear protein, and BrdU and glial fibrillary acidic protein were quantified in the dorsal horn peri-lesion region, and the ipsi- and contralateral sides were compared. A significantly greater number of BrdU/neuron-specific nuclear protein- and BrdU/glial fibrillary acidic protein-colabeled cells were found on the lesion side (P<0.01). These findings led us to hypothesize that neurogenesis can occur within the spinal cord following injury, when the injury does not involve direct trauma to the cord and glial scar formation. This was tested in rats. Neurogenesis and astrocytic proliferation were compared between animals receiving a DRL and those receiving a dorsal column lesion. In DRL rats, neurogenesis was observed in the peri-lesion dorsal horn. In dorsal column lesion rats, no neurogenesis was observed but astrocytic activation was intense. The rat data support our hypothesis and findings in the monkey, and show that the response is not primate specific. The possibility that new neurons contribute to recovery following DRL now needs further investigation.

Abstract

Neurons in hibernating mammals exhibit a dramatic form of plasticity during torpor, with dendritic arbors retracting as body temperature cools and then regrowing rapidly as body temperature rises. In this study, we used immunohistochemical imaging and Western blotting of several presynaptic and postsynaptic proteins to determine the synaptic changes that accompany torpor and to investigate the mechanisms behind these changes. We show torpor-related alterations in synaptic protein localization that occur rapidly and uniformly across several brain regions in a temperature-dependent manner. Entry into torpor is associated with a 50-65% loss of synapses, as indicated by changes in the extent of colocalization of presynaptic and postsynaptic markers. We also show that the loss of synaptic protein clustering occurring during entry into torpor is not attributable to protein loss. These findings suggest that torpor-related changes in synapses stem from dissociation of proteins from the cytoskeletal active zone and postsynaptic density, creating a reservoir of proteins that can be quickly mobilized for rapid rebuilding of dendritic spines and synapses during the return to euthermia. A mechanism of neural plasticity based on protein dissociation rather than protein breakdown could explain the hibernator's capacity for large, rapid, and repeated microstructural changes, providing a fascinating contrast to neuropathologies that are dominated by protein breakdown and cell death.

Abstract

The hand is unique to the primate and manual dexterity is at its finest in the human (Napier 1980), so it is not surprising that cervical spinal injuries that even partially block sensorimotor innervation of the hand are frequently debilitating (Anderson 2004). Despite the clinical need to understand the neuronal bases of hand function recovery after spinal and/or nerve injuries, relatively few groups have systematically related subtle changes in voluntary hand use following injury to neuronal mechanisms in the monkey. Human and macaque hand anatomy and function are strikingly similar, which makes the macaque the favored nonhuman primate model for the study of postinjury dexterity. In this review of monkey models of cervical spinal injury that have successfully related voluntary hand use to neuronal responses during the early postinjury months, the focus is on the dorsal rhizotomy (or dorsal rootlet lesion) model developed and used in our laboratory over the last several years. The review also describes macaque monkey models of injuries to the more central cervical spine (e.g., hemisection, dorsal column) that illustrate methods to assess postlesion hand function and that relate it to neurophysiological and neuroanatomical changes. Such models are particularly important for understanding what the sensorimotor pathways are capable of, and for assessing the outcome of therapeutic interventions as they are developed.

Abstract

Hibernating mammals are remarkable for surviving near-freezing brain temperatures and near cessation of neural activity for a week or more at a time. This extreme physiological state is associated with dendritic and synaptic changes in hippocampal neurons. Here, we investigate whether these changes are a ubiquitous phenomenon throughout the brain that is driven by temperature. We iontophoretically injected Lucifer yellow into several types of neurons in fixed slices from hibernating ground squirrels. We analyzed neuronal microstructure from animals at several stages of torpor at two different ambient temperatures, and during the summer. We show that neuronal cell bodies, dendrites, and spines from several cell types in hibernating ground squirrels retract on entry into torpor, change little over the course of several days, and then regrow during the 2 h return to euthermia. Similar structural changes take place in neurons from the hippocampus, cortex, and thalamus, suggesting a global phenomenon. Investigation of neural microstructure from groups of animals hibernating at different ambient temperatures revealed that there is a linear relationship between neural retraction and minimum body temperature. Despite significant temperature-dependent differences in extent of retraction during torpor, recovery reaches the same final values of cell body area, dendritic arbor complexity, and spine density. This study demonstrates large-scale and seemingly ubiquitous neural plasticity in the ground squirrel brain during torpor. It also defines a temperature-driven model of dramatic neural plasticity, which provides a unique opportunity to explore mechanisms of large-scale regrowth in adult mammals, and the effects of remodeling on learning and memory.

Cuneate nucleus reorganization following cervical dorsal rhizotomy in the macaque monkey: Its role in the recovery of manual dexterityJOURNAL OF COMPARATIVE NEUROLOGYDarian-Smith, C., Ciferri, M.2006; 498 (4): 552-565

Abstract

Immediately following a dorsal rhizotomy that removes input from the thumb, index, and middle fingers, the macaque is unable to execute movements that require controlled apposition of these digits. We have previously shown that within the early weeks and months following one of these lesions, there is 1) a re-emergence of part or all of the cortical hand map; 2) central axonal sprouting of spared primary afferents into the dorsal horn and cuneate nucleus; and 3) substantial although incomplete recovery of hand function (Darian-Smith [204] J. Comp. Neurol. 470:134-150; Darian-Smith and Ciferri [2005] J. Comp. Neurol. 491:27-45). In this study we asked: What neuronal reorganization occurs in the cuneate nucleus during this "recovery" period? And, does it contribute to the recovery of manual dexterity? To address these questions, the representation of the hand was electrophysiologically mapped (by unitary receptive field [RF] recordings) in the pars rotunda of the cuneate nucleus at either 1-2 weeks (short term) or 16-32 weeks (long term) post-rhizotomy. In short-term monkeys, the region deprived of input from the thumb, index, and middle finger was found to be unresponsive to cutaneous stimulation. However, at 16-32 weeks later, when dexterity had largely recovered, RFs of cuneate neurons could again be mapped within the cuneate nucleus, primarily in a region bordering the deprived zone. We conclude that the cuneate pre- and postsynaptic reorganization that occurs following dorsal rhizotomy plays a key role in the recovery of hand function.

Abstract

The recovery of manual dexterity was analyzed in the macaque following a cervical dorsal root section that abolished cutaneous feedback from selected digits of one hand. Monkeys were trained to retrieve a target object from a clamp using thumb and index finger opposition. Dorsal rootlets containing electrophysiologically identified axons projecting from the thumb and index finger were then cut in two monkeys (Group 1). In four others (Group 2), additional rootlets shown to innervate the middle finger and thenar eminence were also transected. Three performance parameters were analyzed before and following the rhizotomy: 1) percentage of successful retrievals; 2) digital stratagem (the pattern of digit opposition); and 3) contact time (duration of digit contact with the object before its retrieval). During the first postoperative week, hand function was severely impaired in all monkeys. Over the following weeks, Group 1 monkeys recovered the ability to retrieve the object by opposing the index finger and thumb in >80% of trials. Group 2 monkeys also regained some function in the impaired hand: each monkey adopted a stratagem for grasping the target, using digits that were incompletely deafferented. In the terminal experiment, hand representation in the contralateral somatosensory cortex was electrophysiologically mapped to define hand deafferentation and cortical reactivation further. There was a close correspondence between the cortical map and digit use. Our data imply that the recovery of precision grip using the thumb and index finger depends on the survival of afferents innervating these digits, as well as the proliferation of their central terminals.

Abstract

We examined the role of primary afferent neurons in the somatosensory cortical "reactivation" that occurs after a localized cervical dorsal root lesion (Darian-Smith and Brown [2000] Nat. Neurosci. 3:476-481). After section of the dorsal rootlets that enervate the macaque's thumb and index finger (segments C6-C8), the cortical representation of these digits was initially silenced but then re-emerged for these same digits over 2-4 postlesion months. Cortical reactivation was accompanied by the emergence of physiologically detectable input from these same digits within dorsal rootlets bordering the lesion site. We investigated whether central axonal sprouting of primary afferents spared by the rhizotomy could mediate this cortical reactivation. The cortical representation of the hand was mapped electrophysiologically 15-25 weeks after the dorsal rootlet section to define this reactivation. Cholera toxin subunit B conjugated to horseradish peroxidase was then injected into the thumb and index finger pads bilaterally to label the central terminals of any neurons that innervated these digits. Primary afferent terminal proliferation was assessed in the spinal dorsal horn and cuneate nucleus at 7 days and 15-25 postlesion weeks. Labeled terminal bouton distributions were reconstructed and the "lesion" and control sides compared within each monkey. Distributions were significantly larger on the side of the lesion in the dorsal horn and cuneate nucleus at 15-25 weeks after the dorsal rootlet section, than those mapped only 7 days postlesion. Our results provide direct evidence for localized sprouting of spared (uninjured) primary afferent terminals in the dorsal horn and cuneate nucleus after a restricted dorsal root injury.

Abstract

The primate red nucleus consists of three main neuron subpopulations, namely, rubrospinal neurons in the magnocellular nucleus, rubroolivary cells in the parvocellular nucleus, and local circuit neurons in both subnuclei: Each subpopulation has unique cerebellar and neocortical inputs. The structural framework for the interactions of these rubral subpopulations remains poorly defined and was the focus of this study in six macaques. Somata of rubrospinal neurons, dorsolateral-spinal (DL-spinal) neurons, as defined in the accompanying paper (Burman et al. [2000] J. Comp. Neurol., this issue), and rubroolivary neurons were labeled retrogradely first with Fast Blue injected either into the cervical spinal cord or the inferior olive. The soma/dendrite profiles of selected cells (53 rubrospinal, 19 DL-spinal, and 17 rubroolivary cells) were visualized by the intracellular injection of Lucifer Yellow/biocytin in fixed slices (400 microm thick) of midbrain. The descriptive statistics of the somata and the dendritic arborization of each rubral neuron type were established. Projection neuron subpopulations had similar but differentiable soma/dendrite profiles, with four to six slender, spine-bearing dendritic trees radiating out approximately 400 microm from the soma. Twelve presumed interneurons, all in the parvocellular nucleus, differed from projection neurons in that they had smaller somata and many slender, spine-bearing segments that constituted the multibranching dendrite profile that radiated out approximately 250 microm from the soma. A tentative model of the macaque rubral microcircuitry was developed, and its functional implications were explored. It incorporated 1) the known topography of the nucleus and its connections, 2) our data specifying the soma/dendrite morphology of the three main rubral neuron types, and 3) the ultrastructure reported by other laboratories of intrarubral synaptic connections.

Abstract

The cerebellar, spinal, bulbar, and cortical connections of the mammalian red nucleus imply a motor role. However, what information the red nucleus receives, processes, and distributes is poorly understood, partly because the rubral microcircuitry, especially in primates, remains incompletely defined. Multiple retrogradely transported fluorescent tracers were injected into the spinal cord and inferior olive of the macaque to label rubrospinal and rubroolivary neuron populations, respectively. Anterograde dextran amines were used to label the terminals of corticorubral neurons. These data provided the topographic framework for examining the morphology of rubral neurons in the accompanying paper (Burman et al. [2000]). Soma profiles of rubrospinal and rubro-olivary neurons were respectively segregated in the magnocellular and parvocellular nuclei. A subpopulation of neurons (DL-spinal cells) with their somas immediately dorsolateral to the rostral magnocellular nucleus and its capsule, also projected to the spinal cord, as did clusters of neurons in the periaqueductal grey matter. Terminals of corticorubral axons originating from ipsilateral primary motor area 4 (the densest projection), the supplementary motor area, cingulate area 24, area 8, and posterior parietal area 5, were each mapped in the parvocellular red nucleus. Only area 4 projected to the magnocellular red nucleus, and this projection as small. DL-spinal neurons had no cortical input. The somatotopic organization of rubral connections was examined only in (a) the corticorubral input from motor area 4, and (b) the rubrospinal and DL-spinal projections. These connections and their somatotopic alignment, were mapped in a 3-dimensional reconstruction of the red nucleus.

Abstract

Chronic peripheral nerve injuries produce neural changes at different levels of the somatosensory pathway, but these responses remain poorly defined. We selectively removed cutaneous input from the index finger and thumb in young adult macaque monkeys by lesioning dorsal rootlets to examine both immediate and long-term systemic responses to this deficit. Corresponding digit representations within somatosensory cortex (SI) were initially silenced, but two to seven months later again responded to cutaneous stimulation of the 'deafferented' digits. We remapped cutaneous receptive fields (RFs) within adjacent intact dorsal rootlets two to four months after lesioning. RF distributions had greatly expanded, so that rootlets previously innervating adjacent hand regions now responded to stimulation of the index finger and/or thumb. Thus our results demonstrate peripherally mediated central reorganization.

Abstract

Transmission of information along appropriately structured parallel pathways ensures that a great deal of information can be transferred from the source to the target very quickly, and with great security-essential features of any motor control system. Studies over the last two decades have established that the corticospinal and corticocerebellar pathways mediating manual dexterity in the primate are structurally organized to sustain the parallel transmission of sensorimotor information in multiple pathways. Serial, hierarchical control systems now seem insufficient to regulate voluntary hand movements. To achieve the required coordination, and precision and speed of execution, they must be combined with parallel control systems, which themselves incorporate elaborate feedforward and feedback controls. To illustrate these issues, two aspects of the structural organization of parallel sensorimotor pathways mediating manual dexterity in the macaque are reviewed. First, we examine the structure of the multiple corticospinal neuron subpopulations projecting from different areas of the frontoparietal cortex and how they are modified following hemisection of the cervical spinal cord. The remarkable recovery of hand function following spinal hemisection, despite the absence of any structural 'bridging' of the interrupted spinal pathways, and the fact that this is accountable in a parallel but not in a purely serial transmission system, are then reviewed. The second aspect of parallel distributed transmission examined is its occurrence within a single population of relay neurons. Our recent structural analysis of the somatic/dendritic organization of rubrospinal neurons in macaque red nucleus is used. The very large dendritic fields of individual neurons, extending over one-third or more of the nucleus, provide a framework for extracting precise somatotopic information from an input population whose axon terminal arbors overlap extensively, and, which, without effective filtering, would provide poor spatial resolution.

Abstract

The detailed morphology of thalamocortical (TC) and corticothalamic (CT) pathways connecting the ventral posterolateral nucleus (VPLc) with the primary somatosensory cortex (areas 3b and 1) and the thalamic pulvinar with the posterior parietal cortex (primarily area 7a), was compared. Each pathway processes information relevant to directed reaching tasks, but whereas VPLc receives its major input from the spinal cord and external environment, the primary afferent to the pulvinar is cortical. Using combined tracer and thick fixed slice procedures, the soma/dendritic morphology of TC neuron populations (with known destination) was shown to be quantitatively similar within VPLc and the pulvinar. This implies that differences in information processing in VPLc (a primary relay) and the pulvinar (an integrative thalamic nucleus) are not defined by a distinctive TC morphology, but rather by the connections of these neuron populations. Two morphologically distinct types of CT axon were observed within the medial pulvinar and VPLc. The more common "Type E" were fine, had boutons en passant and diffuse terminal bifurcations ending in masses of tiny boutons. "Type R" axons were thicker, smooth, and terminated in localised clusters of large terminal boutons. Each type had a unique pattern of termination reflecting a distinct action on target neuron populations. The spatial relationship between TC distribution territories and CT terminal fields was examined within the medial pulvinar and VPLc by using anterograde and retrograde tracers injected together within cortical areas 7a, and 3b/1, respectively. Spatial overlap was incomplete within both thalamic nuclei. Our findings show a more complex relationship between TC and CT neuron populations than previously demonstrated.

Abstract

1. Manual dexterity, of great evolutionary significance to the primates, ranges in complexity from the precise opposition of finger and thumb to Brendal playing Mozart. All dexterity depends on a sustained and rapid transfer of sensorimotor information between the cerebral cortex and the cervical spinal cord. 2. Multiple separate corticospinal neuron populations originate from cortical areas four, the supplementary motor area, anterior cingulate, postarcuate, parietal and insular cortex. Each corticospinal neuron population projects in parallel to all spinal segments, and has a distinctive pattern of terminations. 3. Each corticospinal neuron population has a unique thalamic input which can relay particular sensorimotor information from the sense organs, cerebellum and basal ganglia. The overall structural framework of these sensorimotor pathways, with many parallel corticospinal channels, with interconnections in the cerebral cortex and spinal cord to enable crosstalk between the channels, is that needed for parallel distributed processing, which would enable the very rapid transfer of information between the cerebral cortex and spinal cord needed for any sophisticated use of the hand. 4. Hemisection of the cervical spinal cord in the macaque results in an immediate hemiplegia, with subsequent remarkable although incomplete recovery of hand and finger movements. The only direct corticospinal input to the hemicord caudal to the hemisection, even after 3 years, is the approximately 10% of fibres which cross the midline caudal to the lesion: the fibres 'spared' by the hemisection. A matching 'sparing' of somatosensory input from the paresed limb also occurs. No regeneration of the interrupted pathways has been visualized using modern tracer techniques. 5. Cervical hemisection permanently reduces the number of parallel channels which transmit information between cortex and spinal cord, but does not reduce their cortical origins nor the neuron populations targeted in the spinal cord. We infer that the content of the information that can be transmitted between the cortex and spinal cord is not greatly changed, but the rate of transmission of this information is sharply reduced, and is the 'bottleneck' that limits the complete recovery of dexterity following hemisection. The remarkable recovery that does occur presumably reflects more economic transmission of information by the few spared channels. We guess that this involves substantial synaptic reorganization not visualized by the procedures we have used.

Abstract

In primary sensory and motor cortex of adult animals, alteration of input from the periphery leads to changes in cortical topography. These changes can be attributed to processes that are intrinsic to the cortex, or can be inherited from alterations occurring at stages of sensory processing that are antecedent to the primary sensory cortical areas. In the visual system, focal binocular retinal lesions initially silence an area of cortex that represents the region of retina destroyed, but over a period of months this area recovers visually driven activity. The retinotopic map in the recovered area is altered, shifting its representation to the portion of retina immediately surrounding the lesion. This effectively shrinks the representation of the lesioned area of retina, and expands the representation of the lesion surround. To determine the loci along the visual pathway at which the reorganization takes place, we compared the course of topographic alterations in the primary visual cortex and dorsal lateral geniculate nucleus (LGN) of cats and monkeys. At a time when the cortical reorganization is complete, the silent area of LGN persists, indicating that changes in cortical topography are due to alterations that are intrinsic to the cortex. To explore the participation of thalamocortical afferents in the reorganization, we injected a series of retrogradely transported fluorescent tracers into reorganized and surrounding cortex of each animal. Our results show that the thalamocortical arbors do not extend beyond their normal lateral territory and that this physical dimension is insufficient to account for the reorganization. We suggest that the long-range intrinsic horizontal connections are a likely source of visual input into the reorganized cortical area.

Abstract

Removal of sensory input from a focal region of adult neocortex can lead to a large reorganization of cortical topography within the deprived area during subsequent months. Although this form of functional recovery is now well documented across several sensory systems, the underlying cellular mechanisms remain elusive. Weeks after binocular retinal lesions silence a corresponding portion of striate cortex in the adult cat, this cortex again becomes responsive, this time to retinal loci immediately outside the scotoma. Earlier findings showed a lack of reorganization in the lateral geniculate nucleus and an inadequate spread of geniculocortical afferents to account for the cortical reorganization, suggesting the involvement of intrinsic cortical connections. We investigated the possibility that intracortical axonal sprouting mediates long-term reorganization of cortical functional architecture. The anterograde label biocytin was used to compare the density of lateral projections into reorganized and non-deprived cortex. We report here that structural changes in the form of axonal sprouting of long-range laterally projecting neurons accompany topographic remodelling of the visual cortex.

Abstract

Area 3a in the macaque monkey, located in the fundus of the central sulcus, separates motor and somatosensory cortical areas 4 and 3b. The known connections of areas 4 and 3b differ substantially, as does the information which they receive, process, and transfer to other parts of the central nervous system. In this analysis the thalamic projections to each of these three cortical fields were examined and compared by using retrogradely transported fluorescent dyes (Fast Blue, Diamidino Yellow, Rhodamine and Green latex microspheres) as neuron labels. Coincident labeling of projections to 2-3 cortical sites in each monkey allowed the direct comparison of the soma distributions within the thalamic space of the different neuron populations projecting to areas 3a, 3b, and 4, as well as to boundary zones between these cortical fields. The soma distribution of thalamic neurons projecting to a small circumscribed zone (diameter = 0.5-1.0 mm) strictly within cortical area 3a (in region of hand representation) filled out a "territory" traversing the dorsal half of the cytoarchitectonically defined thalamic nucleus, VPLc (abbreviations as in Olszewski [1952] The Thalamus of the Macaca mulatta. Basel: Karger). This elongate, rather cylindrical, territory extended caudally into the anterior pulvinar nucleus, but not forward into VPLo. The rostrocaudal extent of the thalamic territory defining the soma distribution of neurons projecting to small zones of cortical area 3b was similar, but typically extended into the ventral part of VPLc, filling out a medially concavo-convex laminar space. Two such territories projecting to adjacent zones of areas 3a and 3b, respectively, overlapped and shared thalamic space, but not thalamic neurons. Contrasting with the 3a and 3b thalamic territories, the soma distribution of thalamic neurons projecting to a circumscribed zone in the nearby motor cortex (area 4) did not penetrate into VPLc, but instead filled out a mediolaterally flattened territory extending from rostral VLo, VLm, VPLo to caudal and dorsal VLc, LP, and Pul.o. These territories skirted around VPLc. All three cortical areas 4, 3a, and 3b) also received input from distinctive clusters of cells in the intralaminar Cn.Md. It is inferred that, in combination, the thalamic territories enveloping those neuron somas projecting to, say, the sensorimotor hand representation in areas 3a, 3b, and 4 (and also areas 1 and 2), which would be coactive during the execution of a manual task, constituted a lamellar space extending from VLo rostrally to Pul.o caudally.(ABSTRACT TRUNCATED AT 400 WORDS)

Abstract

In the macaque monkey area 3a of the cerebral cortex separates area 4, a primary motor cortical field, from somatosensory area 3b, which has a subcortical input mainly from cutaneous mechanoreceptive neurons. That each of these cortical areas has a unique thalamic input was illustrated in the preceding paper. In the present experiments the cortical afferent projections to these 3 areas of the sensorimotor cortex monkey were visualized and compared, using 4 differentiable fluorescent dyes as axonal retrogradely transported labels. The cortical projection patterns to areas 3a, 3b, and 4 were similar in that they each consisted of (a) a "halo" of input from the immediately surrounding cortex, and (b) discrete projections from one or more remote cortical areas. However, the pattern of remote inputs from precentral, mesial, and posterior parietal cortex was different for each of the 3 cortical target areas. The cortical input configuration was least complex for area 3b, its remote input projecting mainly from insular cortex. The pattern of discrete cortical inputs to the motor area 4, however, was more complex, with projections from the cingulate motor area (24c/d), the supplementary motor area, postarcuate cortex, insular cortex, and postcentral areas 2/5. Area 3a, in addition to the proximal projections from the immediately surrounding cortex, also received input from the supplementary motor area, cingulate motor cortex, insular cortex, and areas 2/5. Thus, this pattern of cortical input to area 3a resembled more closely that of the adjacent motor rather than that of the somatosensory area 3b. Contrasting with this, however, the thalamic input to area 3a was largely from somatosensory VPLc (abbreviations from Olszewski [1952] The Thalamus of the Macaca mulatta. Basel: Karger) and not from VPLo (with input from cerebellum, and projecting to precentral motor areas).

Abstract

We used several fluorescent dyes (Fast Blue, Diamidino Yellow, Rhodamine Latex Microspheres, Evans Blue, and Fluoro-Gold) in each of eight macaques, to examine the patterns of thalamic input to the sensorimotor cortex of macaques 12 months or older. Inputs to different zones of motor, premotor, and postarcuate cortex, supplementary motor area, and areas 3b/1 and 2/5 in the postcentral cortex, were examined. Coincident labeling of thalamocortical neuron populations with different dyes (1) increased the precision with which their soma distributions could be related within thalamic space, and (2) enabled the detection by double labeling, of individual thalamic neurons that were common to the thalamic soma distributions projecting to separate, dye-injected cortical zones. Double-labeled thalamic neurons projecting to sensorimotor cortex were rarely seen in mature macaques, even when the injection sites were only 1-1.5 mm apart, implying that their terminal arborizations were quite restricted horizontally. By contrast, separate neuron populations in each thalamic nucleus with input to sensorimotor cortex projected to more than one cytoarchitecturally distinct cortical area. In ventral posterior lateral (oral) (VPLo), for example, separate populations of cells sent axons to precentral medial, and lateral area 4, medial premotor, and postarcuate cortex, as well as to supplementary motor area. Extensive convergence of thalamic input even to the smallest zones of dye uptake in the cortex (approximately 0.5 mm3) characterized the sensorimotor cortex. The complex forms of these projection territories were explored using 3-dimensional reconstructions from coronal maps. These projection territories, while highly ordered, were not contained by the cytoarchitectonic boundaries of individual thalamic nuclei. Their organization suggests that the integration of the diverse information from spinal cord, cerebellum, and basal ganglia that is needed in the execution of complex sensorimotor tasks begins in the thalamus.

Abstract

In the present experiments thalamocortical projections to different functional areas of the newborn (or prematurely delivered) macaque's sensorimotor cortex were labeled using retrogradely transported fluorescent dyes. Several dyes were used in each animal to (1) enable the direct comparison of the soma distributions of different thalamocortical projections within thalamic space, and (2) identify by double labeling neurons shared between these distributions. The projection patterns in the newborn macaque were compared with those of the mature animal reported by Darian-Smith et al. (J. Comp. Neurol. 1990;298:000-000). The main observations were (1) all thalamocortical projections to the sensorimotor cortex of the mature macaque are well established by embryonic days 146-150, as was shown by labeling these pathways in infants delivered by cesarean section, (2) a significant number of thalamocortical neurons in the newborn were double-labeled following dye injections into different pre- or postcentral areas, and where the margins of the dye uptake zones were separated by 3-8 mm, and (3) extensive projections from the anterior pulvinar nucleus to the motor and premotor cortex, and to the supplementary motor cortex were labeled in the newborn macaque. Both the exuberant terminal arborizations, and the precentral pulvinar projections were diminished by the 6th postnatal month, and absent in the mature macaque. The role of epigenetic determinants of these postnatal events is briefly considered.

Abstract

Lungs of the human infant and those of other mammals are filled with fluid immediately prior to birth. Studies of the ionic composition of this fluid indicate that active ionic transport processes occur in the epithelial cells of the potential airspaces. The purpose of this study was to see if these active ion pumps were present in developing species other than mammals thus providing a possible evolutionary link to mammals. A series of samples of lung liquid, amniotic fluid, and plasma were taken from embryonic marine turtles gathered from clutches incubating in the beach at Mon Repos, Queensland, Australia during the summer of 1986-87. The concentrations of sodium, potassium and chloride ions and protein measured in these liquids indicated that active pumping processes similar to that seen in the mammalian lung were present in the developing lungs of these marine reptiles and further, circumstantial evidence was gathered to suggest that this liquid was partially reabsorbed prior to hatching. The results support the notion that processes responsible for the normal development of the human lung and lungs of other mammals are also present in the hollow lungs of marine turtles. Thus there is an evolutionary counterpart controlling lung development in more ancient species. It may be possible to generalize this observation to the development of hollow lungs of other species.